Traumatic, asphyxial, hypoxic, ischemic, toxic, infectious, degenerative or metabolic insults to the central nervous system (CNS), peripheral nervous system (PNS) or autonomic nervous system (ANS) often result in damage to several different cell types. Examples on a degenerative condition in the CNS are Parkinson and Alzheimer disease, either of which often causes loss of specific populations of cells. The former is in particular associated with the specific loss of dopaminergic neurons in the substantia nigra. Similarly, multiple sclerosis is associated with structural and functional affection of axons as well as loss of myelin and oligodendrocytes. Another illustration of a degenerative disorder caused by a loss of neurons is Alzheimer's disease. Additionally, there are many instances in which CNS, PNS and ANS injuries or diseases are associated with damage to oligodendroglia, astroglia, satellite cells, Schwann cells, microglia, vascular cells and neurons.
In general, replacement of neurons and differentiated glial cells following the degeneration or damage is not a characteristic of the adult mammalian brain. Neuronal loss is therefore usually considered permanent. However, it must be stressed that the recovery at diseases, brain tumours and neurotrauma mostly is due to repair and rebuilding of the surviving cells. Nonetheless, postnatal neurogenesis persists well into adulthood in all mammalian species, including man, in the subventricular zone (SVZ) at the lateral ventricles in the brain as well as in the subgranular zone (SGZ) in the dentate gyrus in the hippocampus (Ref. 2, 3, 4). Additionally, there is to a minor extent formation of neural progenitor cells in the spinal cord and in the ANS. It has to be stressed that vascular cells, microglial cells and macrophages as well as connective tissue cells may be rebuilt and formed at injuries to and diseases in nervous tissues.
There exists an omnipotent cell population in the brain, named the progenitor cells, as in other tissues in the body of adult mammals, including humans. Neuronal progenitor cells are stem cells and reside in the subventricular zone (SVZ) at the lateral ventricles of the brain and in the subgranular zone (SGZ) of the dentate gyrus in the hippocampus, where such cells continuously proliferate, and migrate into the adjacent brain structures, and eventually either degeneiate or survive and differentiate. The new-born neurons preferentially in e.g. the SGZ migrate into the granule cell layer of the hippocampus and eventually express markers of differentiated neurons and have morphological characteristics corresponding to differentiated granular cells, establish axonal processes into the mossy fibre pathway and form synaptic connections with their targets in the hippocampus. (Ref. 5) It ought to be stressed that a considerable proportion of such newly formed cells may degenerate if not adequately stimulated, while others gain glial cell characteristics (Ref. 3, 4, 5).
The neurogenesis in the dentate gyrus is in itself especially intriguing as the hippocampus is intimately associated with spatial learning and memory (Ref. 6). The neurogenesis in the SVZ is via the rostral migratory stream supplying the olfactory lobe with new nerve cells, but at e.g. stroke and neurotrauma may the migrating primitive neuronal progenitor cells deviate to the injured or diseased site, if situated in reasonable vicinity to the migrating precursor cells.
The proliferation of progenitor cells in the SVZ and in the SGZ are influenced by e.g. the administration of growth factors, interleukines, N-methyl-d-aspartate (NMDA) receptor antagonist or by the removal of the adrenal glands, which latter results in reduced levels of or absence of corticosteroid hormones (Ref. 7, 8). Additionally, the exposure to an enriched environment is accompanied by an increased number of surviving, newly formed granule cells as well as by increased total number of surviving neurons in e.g. the dentate gyrus (Ref.9). The formation of new nerve cells turns reduced with age (Ref. 3).
Diminishing the inflammatory reaction in a nervous tissue after an injury or a disease is beneficiary and results in an increased number of surviving neurons, improved and extended formation of synapses and reduced astrocytosis, concomitant with less hampering effects on the blood vessels and associated structures and thereby the circulation. A weak to moderate inflammation is beneficial with regard to the repair and to restorative events as well as to the neurogenesis, while a strong inflammation is detrimental and may result in an accentuated loss of cells and tissue, that otherwise might have recovered.
The antisecretory factor (AF) is a class of proteins occurring naturally in the body. The common knowledge of the Antisecretory Factor is summarised by Lange & Lönnroth (Ref. 1.). Its structure and some effects exerted by AF in the body of animals, including in man, is described in patent No WO97/08202 (Ref. 10). The humor AF protein is a 41 kD protein, when isolated from the pituitary gland, comprising 382 amino acids.
The active site with regard to anti-inflammatory one antisecretory effects in AF:s is seemingly localized to the protein in a region close to the N-terminal parts of the AF, localized to no 1-163, or more preferably 36-52 or 36-44, or modifications thereof.
Recent studies, performed by the present inventors, have disclosed that AF are to some extent homologous with the protein S5a, also named Rpn 10, which constitute a subunit of a constituent prevailing in all cells, the 26 S proteasome, more specifically in the 19 S/PA 700 cap. In the present invention AF proteins are defined as a class of homologous proteins having the same functional properties. The proteasomes have a multitude of functions related to the degradation of surplus proteins as well as short-lived, unwanted, denatured, misfolded and otherwise abnormal proteins. Further, the AF/S5a/Rpn10 is involved in the distribution and transportation of cell constituents, most evidently proteins.
Davidson and Hickey (Ref. 11, 12) report in two articles published in 2004 in international, scientific journals, that they had generated an antibody against AF, which modulated inflammatory reactions, confirming the statements in the previous patent application and patent (Ref 10, 14).